Anthelmintic preparation

ABSTRACT

A pour-on anthelmintic composition, including its method of preparation and use, the composition preferably having being prepared by mixing at a common temperature (I) a premix of an anthelmintic compound or compounds (for example a benzimidazole) with a transdermal vehicle (such as isopropyl myristate) with (ii) a premix of a non-ionic emulsifier with an oil capable of solubilising the emulsifier and, subsequent to the blending of the premixes (preferably after cooling), mixing the blend with a deflocculation agent/diluent or deflocculation agent/diluent mix.

TECHNICAL FIELD

This invention relates to a method of preparing an anthelminticcomposition and/or an anthelmintic composition (including a preparationso prepared) and/or a method of using such a composition.

BACKGROUND ART

Benzimidazole anthelmintics are widely used orally in aqueous suspensionformulations for the control of parasitic helminths, namely round worms(nematodes), tapeworms (cestodes), or flukes (trematode). Thisanthelmintic group has been used in a variety of animal speciesincluding sheep, cattle, goats, deer, horses, cats, dogs, llama buffaloand poultry. Injectable preparations of benzimidazole anthelmintics arealso known. Benzimidazole anthelmintic compounds are widely used inveterinary medicine. Common forms include oxfendazole, mebendazole,fenbendazole, albendazole and the probenzimidazoles febantel andnetobimin, which are metabolised to benzimidazoles within the animal.

In general, these compounds are sparingly soluble in aqueous solutionsalthough the solubility can be improved by heating the aqueous solution.

Bayer AG British Patent Specification No. 1527584, the full content ofwhich is hereby included by way of reference, refers to the advantagesof pour-on application in veterinary practice over oral treatments andadditionally discloses a pour-on formulation characterised in that theactive compound is dissolved, emulsified or suspended in a suitablesolvent or solvent mixture which is tolerable by the skin (optionallywith addition of further auxiliaries) and applied with the aid of asuitable device, eg. measuring cup or spray bottle to the skin of theanimal to be treated. The active ingredients disclosed are Tetramisoleand Levamisole.

Reference should also be had to the paper "Seasonal Variation andAnthelmintic Response by Cattle to dermally applied Levamisole", B. A.Forsyth et al. Australian Veterinary Journal, Vol. 60 No.5, May 1983 and"Pharmacokinetics of ivermectin after oral or percutaneousadministration to adult milking goats", E. W. Scott et al., JournalVeterinary Pharmacology, Volume 13, pages 432-435, 1990.

E. R. Squibb & Sons Inc, U.S. Pat. No.4,145,433 discloses the option oftopical or parenteral administration to mammalian hosts of benzimidazoledispersed in a non-toxic, non-pyrogenic acceptable carrier. Inparticular it discloses a solution for cutaneous administration beingprepared by dissolving 327 mg of5-(benzyl)sulfinyl!-1H-benzimidazole-2-yl! carbamic acid, methyl esterin a solution of about 4 cc xylene and 1 cc dimethyl sulfoxide. Suchadministrations are stated as being useful in treating infection causedby Haemonchus, Ostertagia, Trichostrongylus, Cooperia, Dictyocaulus,Nematodirus, Bunostomum, Strongyloides, Oesphagostomum, Trichuris andliver flukes at a recommended dosage of from 2.5-25 mg/kg body weight.

DISCLOSURE OF INVENTION

Nevertheless the sparing solubility of anthelmintics restricts their useas pour-ons.

The present invention relates to improved methods of formulatingcompositions of anthelmintics (preferably benzimidazoles) for topical ortransdermal administration to provide a substantially stable compositiondespite any solubility difficulties with the (benzimidazole) activeingredient(s).

It is an object of the present invention to provide a method ofpreparing an alternative anthelmintic composition and/or an anthelminticcomposition and/or a method of using an anthelmintic composition whichwill obviate or minimise the foregoing disadvantages in a simple yeteffective manner or which will at least provide the public with a usefulchoice. More specifically, it is an object of the present invention toprovide alternative veterinary preparations, and/or methods ofpreparation and/or of use of veterinary preparations, whereby preferablybenzimidazole anthelmintics may be applied externally to animals so asto pass into and/or through the skin and into the system(s) eg. blood,lymph and/or tissue! of the animal, providing a simple and quickadministration method which is effective in achieving the necessary doseresponse.

In addition it may provide a simple more prolonged method ofadministering the anthelmintic, increasing the anthelminticseffectiveness.

Accordingly in one aspect the invention consists in a method ofpreparing an anthelmintic composition capable by means of dermalapplication of delivery of a effective anthelmintic amount one or moreactive ingredients into an animal systemically, said method comprising:

(i) mixing at least one anthelmintic compound with a vehicle in whichsaid compound(s) dissolves, suspends and/or emulsifies until thevehicle/active ingredient mixture is substantially homogeneous,

(ii) before, simultaneously with, or after step (i), mixing a non-ionicemulsifier with an oil capable of solubilising the non-ionic emulsifier,said mixing being at a temperature where both the non-ionic emulsifierand oil are in a liquid phase,

(iii) blending the mixtures of steps (i) and (ii) at a temperature atwhich all components are in the liquid phase so as to provide asubstantially homogeneous mixture,

(iv) lowering the temperature, or allowing the lowering of thetemperature, of the mixture of step (iii) while mixing (preferably sothat at least said non-ionic emulsifier is no longer in the liquidphase), and

(v) mixing with the suspension of step (iv) a deflocculation agent/water(or other diluent) mixture to provide the anthelmintic micro suspensionpreparation.

Preferably said anthelmintic active ingredient is at least onebenzimidazole or prodrug therefor.

Other options include an avermectin, pyrantel, morantel, closantel,praziquantel etc.

Preferably said benzimidazole(s) or prodrug thereof is selected from thegroup including oxfendazole, thiabendazole, albendazole, cambenazole,fenbendazole, flubendazole, mebendazole, oxibendazole, parbendazole,thiophanate, febantel and netobimin.

Preferably said benzimidazole(s) is or are oxfendazole and/oralbendazole.

Preferably said benzimidazole(s) is oxfendazole.

Preferably said vehicle is selected from the group including isopropylmyristate, dimethyl sulphoxide, diacetone alcohol,n-methyl-2-pyrrolidone, iso-propyl alcohol, dimethylforamide, and 2pyrrolidone.

Preferably said vehicle is isopropyl myristate.

In addition to said vehicle a cosolvent and/or absorption enhancer isselected from the group including polyoxyethylen glyceroltriricinoleate,polyvinylpyrrolidone, polyoxyethylene - glycerol trihydroxystearate,dimethylformamide (DMF), dimethyl-acetamide, dimethyl isosorbide.

Preferably the mixture of step (i) is elevated in temperature prior tothe blending step (iii).

Preferably the temperature of blending step (iii) is from about 55° C.to about 60° C.

Preferably the oil of step (ii) capable of solubilising the non-ionicemulsifier is a mineral oil or a vegetable oil.

Preferably said oil is selected from the group consisting of rapeseed orcanola oil, polyol fatty acid ester, lauric acid hexyl, oleic acid decylester, 2-octyl dodecanol soybean, sunflower oil, and ground nut refinedfixed oils.

Preferably said non-ionic emulsifier of step (ii) is selected from thegroup including sorbitan stearate, polysorbates including ethoxy (20)sorbitan monopalmitate, ethoxy (20) sorbitan monostearate, ethoxy (4)sorbitan monostearate and ethoxy (20) sorbitan tristearate!,polyoxyethylene castor oils and polyoxyethylene glycols.

Preferably said non-ionic emulsifier of step (ii) is sorbitan stearate.

Preferably the step (ii) is carried out at an elevated temperature.

Preferably said elevated temperature at which step (ii) is carried outis from about 55°C. to about 60° C.

Preferably the blending step (iii) is carried out only after thesubstantially homogeneous mixture of step (i) has been raised to atemperature of from about 55 ° C to about 60° C.

Preferably the temperature lowering step (iv) is to room or ambienttemperature(s).

Preferably the deflocculation agent/water mixture is of a deflocculationagent selected from the group consisting of sodium lignosulphonate,silicon dioxides, poly vinyl pyrrolidones and/or said diluent is water.

Preferably said deflocculation agent is sodium lignosulphonate.

Preferably said deflocculation agent/water mixture has been mixed with asonic mixing procedure.

Preferably said deflocculation agent/water mixture is added to themixture of step (iv) substantially at room or ambient temperatures.

Preferably the composition comprises

    ______________________________________    Oxfendazole      7.5% w/v    Iso Propyl Myristate                     66.0% w/v    Sorbitan Stearate                     1.0% w/v    Sodium Lignosulphonate                     0.9% w/v    Canola Oil       0.5% w/v    Deionised Water  Up to the 100%.    ______________________________________

Preferably said mixture includes at least one or more of the followingcompounds, a trace mineral or trace minerals, a synthetic pyrethroid orpyrethroids (eg; cypermethrin), an organic phosphate ororganophosphates, closantel pyrantel morantel, praziquantel andsynthetic pyrethroids.

Preferably any such optional trace mineral(s) organophosphate(s) and/orclosantel sodium is mixed into

(a), in the case of trace mineral(s) the pre-mix of step (iv) or (v),

(b), in the case of any organophosphate(s), in a mix of step (iv) or(v),

(c) in the case of closantel sodium, a mix of step (i),

(d) in the case of pyrantel or morantel, a mix of step (i),

(e) in the case of praziquantel a mix of step (i),

(f) in the case of synthetic pyrethroid(s), a mix of step (i).

In a further aspect the invention is a benzimidazole anthelminticcomposition prepared by a method as previously defined.

In still a further aspect the invention consists in an anthelminticcomposition capable of being used transdermally such as by a pour-onprocedure, said composition comprising at room or ambient temperature

at least one benzimidazole or prodrug thereof dissolved in, suspended onand/or emulsified by a transdermal vehicle and a liquid carrier for suchbenzimidazole/vehicle which includes a non-ionic emulsifier, an oilwhich solubilises the non-ionic emulsifier, water or other suitablediluent and a deflocculation agent.

Preferably said composition comprises

    ______________________________________    Benzimidazole(s)        1% to 50% w/v,    Transdermal vehicle(s)                            2% to 80% w/v,    Non-ionic emulsifier(s)                          0.1% to 10% w/v,    Oil(s)                0.1% to 10% w/v,    Deflocculation agent(s)                          0.1% to 10%, and    Water or other suitable diluent                            5% to 50% w/v.    ______________________________________

Preferably said benzimidazole or prodrug thereof is selected from thegroup consisting of oxfendazole, thiabendazole, albendazole,cambenazole, fenbendazole, flubendazole, mebendazole, oxibendazole,parbendazole, thiophanate, febantel and netobimin,

said vehicle is selected from the group including isopropyl myristate,dimethyl sulphoxide, diacetone alcohol, n-methyl-2-pyrrolidone and 2pyrrolidone,

said oil is selected from the group including rapeseed or canola oil,polyol fatty acid ester, lauric acid hexyl, oleic acid decyl ester,2-octyl dodecanol, soybean, sunflower oil, cold pressed rapeseed andground nut refined fixed oils.

said non-ionic emulsifier is selected from the group including sorbitanstearate, polysorbates, polyoxyethylene castor oils and polyoxyethyleneglycols and

said deflocculation agent is selected from the group including sodiumlignosulphonate, silicon dioxides, poly vinyl pyrrolidones.

Preferably said benzimidazole is oxfendazole, said vehicle is isopropylmyristate, said oil is rapeseed or canola oil said non-ionic emulsifieris sorbitan stearate and said deflocculation agent is sodiumlignosulphonate.

Preferably said composition comprises

    ______________________________________    Oxfendazole      7.5% w/v    Iso Propyl Myristate                     66.0% w/v    Sorbitan Stearate                     1.0% w/v    Sodium Lignosulphonate                     0.9% w/v    Canola Oil       0.5% w/v    Deionised Water  up to the 100%.    ______________________________________

Preferably the composition additionally includes at least one tracemineral and/or at least one organo phosphate and/or closantel sodium.

In still a further aspect the invention consists in a method ofcontrolling helminth(s) (nematode, cestode or trematode) within ananimal which comprises applying to the skin of the animal ananthelmintic composition as herein defined and thereafter allowing atleast the anthelmintic compound(s) preferably benzimidazole or prodrugcompound(s)! to pass through and/or into the skin of the animal to enterthe blood, lymph and/or tissue fluids of the animal in ananthelmintically effective amount.

Preferably said composition is applied by a pour-on procedure or othermethod of skin application.

Preferably said composition is about a 75 mg/mL suspension ofoxfendazole at about a dosage rate oxfendazole/weight of animal at leasttwice that recommended for oral administration currently beingrecommended for oxfendazole anthelmintic treatment of any such animal.

Preferably said composition is about a 75 mg/mL suspension ofoxfendazole at a dosage rate of about 10 mg oxfendazole/kg body weightof the animal.

Preferably the animal is a ruminant but can be other mammals or even nonmammals.

Preferably said veterinary preparation also includes a surface activedispersant or wetting agent.

In a further aspect the invention consists in an anthelminticcomposition capable by dermal application to an animal of delivering ananthelminticly effective amount of systemic anthelmintic activeingredient into the animal

    ______________________________________    systemic anthelmintic compound(s)                           1% to 50% w/v,    emulsifier           0.1% to 10% w/v,    carrier solvent (transdermal vehicle)                           2% to 80% w/v,    dispersant or wetting agent                         0.1% to 10% w/v,    oil                  0.1% to 10% w/v, and    diluent                5% to 50% w/v.    ______________________________________

Preferably said anthelmintic compound is a benzimidazole.

BRIEF DESCRIPTION OF DRAWINGS

The invention also consists in methods of use thereof.

The present preferred forms of the invention will now be described. Theaccompanying drawing (FIG. 1) is a plot of helminth egg counts againsttime.

BEST MODE(S) FOR CARRYING OUT THE INVENTION

According to the invention, a veterinary preparation is provided, alongwith a method of preparing a veterinary preparation, and a method ofusing a veterinary preparation.

The preparation is so formulated as to be suitable for dermal use, e.g.spread on, spray on, or pour-on (hereinafter "pour-on"). The inventionis that the benzimidazole anthelmintic is presented in a carrier orsolvent (hereafter "vehicle") which is capable of being absorbed throughthe skin. By preference, this vehicle is iso propyl myristate, althoughother compounds may be substituted, for example, dimethyl sulphoxide,diacetone alcohol, N-methyl-2-pyrrolidone, 2 pyrrolidone or othersuitable non-toxic compounds which can be absorbed through the skin ofthe target animals. Thus the formulation when applied externally to theanimal will pass through the skin and into the systems of the animalwhere it can take effect.

A typical formulation according to the invention consists of 1% to 50%w/v benzimidazole, 2% to 80% w/v vehicle, 5% to 50% w/v diluent, 0.1% to10% w/v non-ionic emulsifier, 0.1% to 10% w/v deflocculant and 0.1% to10% oily component.

The emulsifier in the preferred form of the invention is sorbitanstearate but this may be substituted by other non-ionic emulsifiers, forexample, polysorbates, polyoxyethylene castor oils, polyoxyethyleneglycols.

The dispersant or wetting agent is in the preferred form of theinvention sodium lignosulphonate, but this may be substituted by silicondioxides, poly vinyl pyrrolidones, or other surface active agents.

The preparation also contains an oily component. In the most presentlypreferred form of the invention, this is rapeseed oil but this may besubstituted by polyol fatty acid ester, lauric acid hexyl, oleic aciddecyl ester, 2-octyl dodecanol or other vegetable oils such as soybeanor sunflower oil.

The preparation is made up to volume with a diluent, such as deionisedwater. This diluent may be substituted by or include or be (any one ormore) other miscible diluents such as propylene glycol, sorbitol orglycerol.

EXAMPLE

    ______________________________________    Oxfendazole      7.5% w/v    Iso Propyl Myristate                     66.0% w/v    Sorbitan Stearate                     1.0% w/v    Sodium Lignosulphonate                     0.9% w/v    Rapeseed Oil     0.5% w/v    Deionised Water  Up to the 100%.    ______________________________________

Other, anthelmintic or therapeutic substances may also be included inthe preparation if desired, for example, minerals, trace elements,synthetic pyrethroids and organophosphates.

The composition of the present may be prepared as follows:

The benzimidazole anthelmintic, for example oxfendazole, is added to thecarrier solvent, for example iso propyl myristate, and the two compoundsare mixed until the mixture is thoroughly wetted.

The non-ionic emulsifier, for example sorbitan stearate is then added tothe mixture while maintaining stirring, followed, while continuing tostir, by the dispersant or wetting agent, for example sodiumlignosulphonate, and the suitable oily component, for example rapeseedor canola oil. The mixture is then made up to volume with the diluent,for example deionised water. The total mixture is then continued to bemixed until it is substantially homogeneous.

The more preferred procedure is

(i) mixing at least one anthelmintic compound (eg: oxfendazole) with avehicle (eg: isopropyl myristate) in which said compound(s) dissolves,suspends and/or emulsifies until the vehicle/active ingredient mixtureis substantially homogeneous,

(ii) before, simultaneously with, or after step (i), mixing a non-ionicemulsifier (eg: sorbitan stearate) with an oil (eg: rapeseed oil)capable of solubilising the non-ionic emulsifier, said mixing being at atemperature (preferably elevated to 55° C. to 60° C.) where both thenon-ionic emulsifier and oil are in a liquid phase,

(iii) blending the mixtures of steps (i) and (ii) at a temperature(preferably elevated to 55° C. to 60° C.) at which all components are inthe liquid phase so as to provide a substantially homogeneous mixture,

(iv) lowering the temperature, or allowing the lowering of thetemperature, of the mixture of step (iii) (eg: to room or ambienttemperature) while mixing so that at least said non-ionic emulsifier isno longer in the liquid phase, and

(v) mixing with the suspension of step (iv) a deflocculationagent/diluent mixture (eg: sodium lignosulphate/water) to provide theanthelmintic micro suspension preparation, said diluent being selectedfrom the group comprising water, propylene glycol sorbitol and glycerol.

This procedure provides an anthelmintic composition which over time canprovide most effective helminth control.

The following eleven formulations give examples of differentformulations within the present invention.

    ______________________________________    FORMULATION 1    Oxfendazole           7.5%        w/v    Iso Propyl Myristate  66.0%       w/v    Canola Oil            0.5%        w/v    Liposorb S            1.0%        w/v    Sodium Lignosulphonate                          0.9%        w/v    Benzyl Alcohol        5.0%        w/v    Deionised Water       qs to 100%  v/v    FORMULATION 2    Albendazole           7.5%        w/v    Iso Propyl Myristate  66.0%       w/v    Canola Oil            0.5%        w/v    Liposorb S            1.0%        w/v    Sodium Lignosulphonate                          0.9%        w/v    Benzyl Alcohol        5.0%        w/v    Deionised Water       qs to 100%  v/v    FORMULATION 3    Fenbendazole          2.5%-10%    w/v    Iso Propyl Myristate  66.0%       w/v    Canola Oil            0.5%        w/v    Liposorb S            1.0%        w/v    Sodium Lignosulphonate                          0.9%        w/v    Benzyl Alcohol        5.0%        w/v    Deionised Water       qs to 100%  v/v    FORMULATION 4    Oxfendazole           7.5%        w/v    Closantel - Sodium    2.5% w/v-5.0%                                      w/v    Iso Propyl Myristate  66.0%       w/v    Canola Oil            0.5%        w/v    Liposorb S            1.0%        w/v    Sodium Lignosulphonate                          0.9%        w/v    Benzyl Alcohol        5.0%        w/v    Deionised Water       qs to 100%  v/v    FORMULATION 5    Praziquantel          2.5%        w/v    Oxfendazole           7.5%        w/v    Iso Propyl Myristate  66.0%       w/v    Canola Oil            0.5%        w/v    Sodium Lignosulphonate                          0.9%        w/v    Liposorb S            1.0%        w/v    Benzyl Alcohol        5.0%        w/v    Deionised Water       qs to 100%  v/v    FORMULATION 6    Oxfendazole           7.5%        w/v    Cypermethrin          2.5%        w/v    Iso Propyl Myristate  66.0%       w/v    Canola Oil            0.5%        w/v    Sodium Lignosulphonate                          0.9%        w/v    Benzyl Alcohol        5.0%        w/v    Liposorb S            1.0%        w/v    Deionised Water       qs to 100%  v/v    FORMULATION 7    Oxfendazole           7.5%        w/v    Iso Propyl Myristate  66.0%       w/v    Canola Oil            0.5%        w/v    Sodium Lignosulphonate                          0.9%        w/v    Benzyl Alcohol        5.0%        w/v    Liposorb S            1.0%        w/v    Copper Disodium Ethylenediamine                          10.7%       w/v    Tetra Acetate    Zinc EDTA             5.4%        w/v    Cobalt EDTA           1.1%        w/v    Sodium Selenate       0.57%       w/v    EDDI                  0.57%       w/v    Deionised Water       qs to 100%  v/v    FORMULATION 8    Benzimidazole(s)      1%-20%      w/v    Transdermal Vehicle(s)                          2%-80%      w/v    Non-ionic Emulsifier(s)                          0.1%-10%    w/v    Oil(s)                0.1%-10%    w/v    Deflocculation Agent(s)                          0.1%-10%    w/v    Preservative(s)       0.5%-10%    w/v    Water or suitable diluent                          1%-50%      v/v    FORMULATION 9    Benzimidazole(s)      1%-20%      w/v    Anthelmintic(s)       1%-5%       w/v    Transdermal Vehicle(s)                          2%-80%      w/v    Non-ionic Emulsifier(s)                          0.1%-10%    w/v    Oil(s)                0.1%-10%    w/v    Deflocculation Agent(s)                          0.1%-10%    w/v    Preservative(s)       0.5%-10%    w/v    Water or other suitable diluent                          1%-50%      v/v    FORMULATION 10    Benzimidazole(s)      1%-20%      w/v    Pyrethroid(s)         1%-5%       w/v    Transdermal Vehicle(s)                          2%-80%      w/v    Non-ionic Emulsifier(s)                          0.1%-10%    w/v    Oil(s)                0.1%-10%    w/v    Deflocculation Agent(s)                          0.1%-10%    w/v    Preservative(s)       0.5%-10%    w/v    Water or other suitable dilutent                          1%-50%      v/v    FORMULATION 11    Anthelmintic(s) (including Benzimidazole(s))                          1%-20%      w/v    Transdermal Vehicle(s)                          2%-80%      w/v    Non-ionic Emulsifier(s)                          0.1%-10%    w/v    Oil(s)                0.1%-10%    w/v    Deflocculation Agent(s)                          0.1%-10%    w/v    Trace Mineral(s)      1%-25%      w/v    Preservative(s)       0.5%-10%    w/v    Water or other suitable dilutent                          1%-50%      v/v    ______________________________________

This formulation may be administered to cattle, for example, in volumedosages of 35-45 mls for cattle of 250-310 kg body weight. Of courseveterinary advice should also be sought regarding dosages. Dosages insimilar ratios are applicable to other animals, eg: sheep, goats,horses, deer, cats, dogs, camel, llama and buffalo.

Thus it can be seen that an improved benzimidazole anthelminticpreparation, a method of preparing a veterinary preparation, and amethod of using a veterinary preparation are provided by the inventionin its preferred form which have the advantage of increasing theconvenience and effectiveness of use of such compounds, throughproviding for efficacious dermal application.

Thus the formulation when applied externally will pass into and/orthrough the skin and be transported by the blood, lymph or tissue fluidsto act on the helminth (nematode, cestode or trematode) both within bodytissues and body organs including muscle, lung, liver and kidney andwithin the lumen of both the gastrointestinal and respiratory tract.

The mechanism of action of the benzimidazole anthelmintics on helminthsis believed to be due to their disruption of intracellular microtubulartransport systems by binding selectively to and damage of, helminthtubulin, preventing tubulin polymerisation and the inhibition ofmicrotubule formation. Benzimidazoles have also been shown to act athigher levels as inhibitors of metabolic enzymes, including malatedehydrogenase and fumarate reductase, and disrupt metabolic pathwayswithin the helminth. Orally Benzimadazoles appear to be most effectiveas anthelmintics (drenches) when given over several days rather than asan oral single dose.

The preparation may be applied may be applied according to theinvention, dermally, eg. as a pour-on on to the mid line of the back orneck of animals such as cattle. The active ingredient (ie. theanthelmintic) is absorbed through the skin and into the blood, tissuesand tissue fluids of the animal.

Data based on the application of the said pour on, in this caseoxfendazole, at 2.2 times the oral dose rate (ie. 10 mg/kg) producedblood serum levels up to 0.2 μg/mL which is comparable with the bloodlevels seen in calves orally administered with oxfendazole at a doserate of 4.5 mg/kg. Blood oxfendazole levels in the said pour on calveswere generally lower and unexpectedly persistent, with low levels ofoxfendazole detected in their blood at day 3 and 4 after administration.Blood levels in calves that received oral oxfendazole were belowdetection (0.025 μg/mL) at day 3.

A slower action was also seen in the reduction of faecal egg counts inthe pour on group with significant reductions on day 2 and 3 aftertreatment compared with a significant reduction occurring at day 1 and 2in the oral group (see FIG. 1).

FIG. 1 shows Faecal Egg Counts (F.E.C's) in Eggs per gram (EPG) in 6month old Friesan Calves, treated with oral oxfendazole(Synanthic`.sup.™) at a dose rate of 4.5 mg per kg, the trialoxfendazole pour-on at 10.0 mg/kg and untreated control animals.Treatment was at day 0.

The pour-on formulation used for these FEC/Time trials was

    ______________________________________    Oxfendazole      7.5% w/v    Iso Propyl Myristate                     66.0% w/v    Sorbitan Stearate                     1.0% w/v    Sodium Lignosulphonate                     0.9% w/v    Canola Oil       0.5% w/v    Deionised Water  Up to the 100%.    ______________________________________

It has already been demonstrated that treatment regimes that providemore prolonged levels of benzimidazoles over a number of days such asappear to be demonstrated in this pour on product, increases theeffectiveness of the anthelmintic.

Table 1 is a comparison of Faecal Egg Counts (F.e.c's) in 6 Month OldFriesan Calves Treated with Oral Oxfendazole (Synanthic™) At 4.5 Mg/Kgand Trial Pour Oxfendazole Product At 13.5 Mg/kg.

                  TABLE 1    ______________________________________    Oxfendazole Pour-on    Animal Treatment               mean:    No     Group     Day 1   Day 0 -1,0  Day 7 Day 14    ______________________________________    2      Control   --      0     0     0     100    5      Control   50      100   75    0     0    10     Control   100     200   150   100   300    12     Control   50      50    50    100   50    25     Control   500     300   400   200   400    33     Control   500     150   325   0     0    51     Control   200     0     100   450   300    58     Control   50      0     25    200   150    59     Control   450     400   425   400   600    70     Control   50      150   100   100   N.D.    geometric        217     135   165   150   211    means    1      Oral      50      100   75    0     0    3      Oral      200     200   200   50    0    6      Oral      50      200   125   50    0    8      Oral      50      50    50    0     0    11     Oral      350     50    200   0     0    13     0ral      50      50    50    0     0    16     Oral      350     100   225   0     0    30     Oral      300     250   275   0     50    36     Oral      200     300   250   50    0    38     Oral      100     50    75    0     0    41     Oral      300     200   250   0     0    45     Oral      100     0     50    0     0    47     Oral      500     300   400   0     0    55     Oral      50      150   100   0     0    61     Oral      350     500   425   50    50    62     Oral      300     50    175   0     0    66     Oral      50      50    50    0     0    73     Oral      50      0     25    0     0    74     Oral      400     0     200   0     50    geometric        190     139   168   10    8    mean    4      Pour-on   50      0     25    0     0    7      Pour-on   230     0     125   0     0    9      Pour-on   150     --    75    0     0    14     Pour-on   100     100   100   0     0    18     Pour-on   150     100   125   0     0    20     Pour-on   50      0     25    0     0    21     Pour-on   100     250   175   0     50    22     Pour-on   100     100   100   0     0    23     Pour-on   50      100   75    0     0    26     Pour-on   50      0     25    0     0    28     Pour-on   350     500   425   0     0    31     Pour-on   850     400   625   0     0    37     Pour-on   100     50    75    0     0    40     Pour-on   150     350   250   0     0    42     Pour-on   150     150   150   0     50    44     Pour-on   400     0     200   0     0    50     Pour-on   900     1550  1225  200   750    57     Pour-on   50      0     25    0     0    60     Pour-on   50      50    50    0     0    76     Pour-on   50      0     25    0     0    geometric        205     195   195   10    42    mean    ______________________________________

SUMMARY

Comparison of oral and pour-on formulations. Treatment groups are: Group0=untreated controls, Group 1=oral drench, and Group 3=pour-onformulation

Note: All analyses were carried out on log-transformed FEC's.

The analysis of faecal egg counts (FEC's) shows that there were nosignificant differences between any of the groups either on day -1 orday 0. Subsequently, on days 7, 14 and 21 post-treatment there was ahigh significant difference between the untreated control group and thegroups treated with oxfendazole (p<0.0001). There were no significantdifferences between the orally or topically treated groups.

We claim:
 1. A method of preparing a composition of a benzimidazoleanthelmintic compound or pro-drug thereof which is effective by dermalapplication to a mammal of delivery of the benzimidazole compound orpro-drug thereof systemically into the mammal to elicit an anthelminticresponse, said method comprising:(i) mixing at least one anthelminticbenzimidazole compound or pro-drug thereof with an organic transdermalvehicle into which said benzimidazole compound or pro-drug thereofsubstantially dissolves, suspends and/or emulsifies, said benzimidazolecompound or pro-drug thereof being substantially insoluble in water andbeing a solid at room or temperate ambient temperatures; (ii) before,simultaneously with, or after step (i), mixing an organic non-ionicemulsifier with an oil capable of solubilizing the non-ionic emulsifierat least above room or temperate ambient temperatures, said mixturebeing at a temperature or temperatures where both the non-ionicemulsifier and the oil are in a liquid phase; (iii) blending themixtures of steps (i) and (ii) at a temperature or temperatures at whichthe organic transdermal vehicle, the oil and the organic non-ionicemulsifier are in the liquid phase so as to provide a substantiallyhomogeneous organic phase mixture which includes, in particulate form,the benzimidazole compound or pro-drug thereof; (iv) lowering thetemperature, or allowing the lowering of the temperature, of the organicphase mixture of (iii) while mixing so that at least said non-ionicemulsifier in addition to said benzimidazole compound or pro-drugthereof is no longer in the liquid phase, and (v) mixing with thesuspension of step (iv) a deflocculation agent/diluent mixture toprovide a micro suspension, said diluent being selected from water,propylene glycol, sorbitol and glycol but with the proviso that water isselected.
 2. A method of claim 1 wherein said benzimidazole(s) orpro-drug thereof is or are selected from the group consisting ofoxfendazole, thiabendazole, albendazole, cambendazole, fenbendazole,flubendazole, mebendazole, oxibendazole, parbendazole, thiophanate,febantel and netobimin.
 3. A method as claimed in claim 2 wherein saidbenzimidazole(s) is oxfendazole.
 4. A method as claimed in claim 1wherein said organic transdermal vehicle is selected from the groupconsisting of isopropyl myristate, dimethyl sulphoxide, diacetonealcohol n-methyl-2-pyrrolidone, dimethyl formamide and 2-pyrrolidone. 5.A method as claimed in claim 4 wherein said organic transdermal vehicleis isopropyl myristate.
 6. A method as claimed in claim 1 wherein thetemperature of the mixture of step (i) is elevated prior to the blendingstep (iii).
 7. A method as claimed in claim 6 wherein the temperature ofthe blending step (iii) is from 55° C. to 60° C.
 8. A method as claimedin claim 1 wherein the oil of step (ii) is a mineral oil or a vegetableoil.
 9. A method as claimed in claim 8 wherein said oil is selected fromthe group consisting of canola oil, rapeseed oil, polyol fatty acidester, lauric acid hexyl ester, oleic acid decyl ester, 2-octyldodecanol, soybean and sunflower oil.
 10. A method as claimed in claim 1wherein said non-ionic emulsifier of step (ii) is selected from thegroup consisting of sorbitan stearate, polysorbates, polyoxyethylenecastor oils and polyoxyethylene glycols.
 11. A method as claimed inclaim 10 wherein said non-ionic emulsifier of step (ii) is sorbitanstearate.
 12. A method as claimed in claim 1 wherein the step (ii) iscarried out at an elevated temperature.
 13. A method as claimed in claim12 wherein said elevated temperature at which step (ii) is carried outis from 55° C. to 60° C.
 14. A method as claimed in claim 1 wherein theblending step (iii) is carried out only after the substantiallyhomogeneous mixture of step (i) has been raised to a temperature of from55° C. to 60° C.
 15. A method as claimed in claim 1 wherein thetemperature lowering step (iv) is to room or temperate ambienttemperature(s).
 16. A method as claimed in claim 1 wherein thedeflocculation agent is selected from the group consisting of sodiumlignosulphonate, silicon dioxides, poly vinyl pyrrolidones and saiddiluent is water.
 17. A method as claimed in claim 16 wherein saiddeflocculation agent is sodium lignosulphonate.
 18. A method as claimedin claim 16 wherein said deflocculation agent/water mixture has beenmixed with a sonic mixing procedure.
 19. A method as claimed in claim 18wherein said deflocculation agent/water mixture is added to the mixtureof step (iv) substantially at room or temperate ambient temperature(s).20. A method as claimed in claim 1 wherein the composition comprises:

    ______________________________________    Oxfendazone      7.5% w/v    Iso Propyl Myristate                     66.0% w/v    Sorbitan Stearate                     1.0% w/v    Sodium Lignosulphonate                     0.9% w/v    Canola Oil       0.5% w/v    Deionized Water  Up to the 100%.    ______________________________________


21. A method as claimed in claim 1 wherein said composition furthercomprises at least one compound selected from the group consisting of atrace mineral or trace minerals, synthetic pyrethroid or pyrethroids, anorganic phosphate or organo phosphate and closantel sodium.
 22. A methodas claimed in claim 21 wherein said trace mineral(s), organophosphate(s) and/or closantel sodium is mixed into(a) in the case oftrace mineral(s) the premix of step (iv) or (v); (b) in the case of anyorganic phosphate(s), in a mix of step (iv) or (v); (c) in the case ofclosantel sodium, a mix of step (i); (d) in the case of pyrantel ormorantel, a mix of step (i); (e) in the case of praziquantel, a mix ofstep (i); and (f) in the case of synthetic pyrethroid(s), a mix of step(i).
 23. A method as claimed in claim 10 wherein the non-ionicemulsifier of step (ii) is ethoxy (20) sorbitan monopalmitate, ethoxy(20) sorbitan monostearate, ethoxy (4) sorbitan monostearate or ethoxy(20) sorbitan tristearate.
 24. An anthelmintic composition prepared by amethod as claimed in claim
 1. 25. An anthelmintic composition capable ofbeing applied by a pour-on procedure to an animal to deliver asystemically effective anthelmintic amount of the active ingredientbenzimidazole or pro-drug thereof, said composition comprising at roomor temperate ambient temperature(s) at least one benzimidazole orpro-drug thereof dissolved in, suspended in and/or emulsified by anorganic transdermal vehicle and a liquid carrier for such benzimidazoleor pro-drug thereof/vehicle which comprises a non-ionic emulsifier, anoil which can solubilize the non-ionic emulsifier at elevatedtemperatures, water, and a deflocculation agent.
 26. A composition asclaimed in claim 25 comprising:

    ______________________________________    Benzimidazole(s)    1% to 50% w/v    Transdermal vehicle(s)                        2% to 80% w/v    Non-ionic emulsifier(s)                        0.1% to 10%                                  w/v    Oil(s)              0.1 to 10%                                  w/v    Deflocculation agent(s)                        0.1 to 10%                                  w/v    Water or other suitable                        5% to 50% w/v.    diluent    ______________________________________


27. A composition as claimed in claim 25 wherein said benzimidazole orpro-drug thereof is selected from the group consisting of oxfendazole,thiabendazole, albendazole, cambendazole, fenbendazole, flubendazole,mebendazole, oxibendazole, parbendazole, thiophanate, febantel, andnetobimin,said vehicle is selected from the group consisting ofisopropyl myristate, dimethyl sulphoxide, diacetone alcohol,n-methyl-2-pyrrolidone, and 2-pyrrolidone, said oil is selected from thegroup consisting of canola oil, polyol fatty acid ester, lauric acidhexyl ester, oleic acid decyl ester, 2-octyl dodecanol, soybean andsunflower oil, rapeseed, and ground nut refined fixed oils, saidnon-ionic emulsifier is selected from the group consisting of sorbitanstearate, polysorbates, polyoxyethylene castor oils and polyoxyethyleneglycols and said deflocculation agent is selected from the groupconsisting of sodium lignosulphonate, silicon dioxides polyvinylpyrrolidones.
 28. A composition as claimed in claim 25 wherein saidbenzimidazole is oxfendazole, said vehicle is isopropyl myristate, saidoil is canola oil, said non-ionic emulsifier is sorbitan stearate andsaid deflocculation agent is sodium lignosulphonate.
 29. A compositionas claimed in claim 25 which comprises:

    ______________________________________    Oxfendazole      7.5% w/v    Iso Propyl Myristate                     66.0% w/v    Sorbitan Stearate                     1.0% w/v    Sodium Lignosulphonate                     0.9% w/v    Canola Oil       0.5% w/v    Deionized Water  Up to the 100%.    ______________________________________


30. A composition as claimed in claim 25 which further comprises atleast one trace mineral and/or at least one organo phosphate and/orclosantel sodium and/or praziquantel and/or pyrantel, and/or morantel,and/or synthetic pyrethroids.
 31. A composition of claim 27 wherein thenon-ionic emulsifier is ethoxy (20) sorbitan monopalmitate, ethoxy (20)sorbitan monostearate, ethoxy (4) sorbitan monostearate or ethoxy (20)sorbitan tristearate.
 32. An anthelmintic composition capable by dermalapplication to an animal of delivering an anthelmintically effectiveamount of a benzimidazole or pro-drug thereof into the animal whichcomprises:

    ______________________________________    at least one benzimidazole or pro-drug thereof                          1% to 50% w/v;    a non-ionic emulsifier                          0.1% to 10%                                    w/v;    an organic transdermal vehicle                          2% to 80% w/v;    a dispersant or wetting agent                          0.1 to 10%                                    w/v;    an oil suitable for solubilizing the non-ionic                          0.1% to 10%                                    w/v; and    emulsifier    water                 5% to 50% w/v.    ______________________________________


33. A method of controlling helminth(s) within a non-human animal whichcomprises applying to the skin of the animal a composition as claimed inclaim 25 and thereafter allowing at least the active anthelminticcompound(s) to pass through and/or into the skin of the animal to enterthe blood, lymph and/or tissue fluids of the animal in ananthelmintically effective amount.
 34. A method as claimed in claim 33wherein said composition is applied by a pour-on procedure.
 35. A methodas claimed in claim 34 wherein said composition is about a 75 mg/mLsuspension of oxfendazole applied at about a dosage rateoxfendazole/weight of the animal of at least twice the oraladministration dosage were oxfendazole orally administered as ananthelmintic treatment of such an animal.
 36. A method as claimed inclaim 34 wherein said composition is about a 75 mg/mL suspension ofoxfendazole applied at a dosage rate of about 10 mg oxfendazole/kg bodyweight of the animal.
 37. A method as claimed in claim 33 wherein theanimal is a ruminant.